Diquaternary compounds and the manufacture thereof



United States Patent DIQUATERNARY COMPOUNDS AND THE MANUFACTURE THEREOF John Evlyn Warner Billingllurst, London, England, as-

signor to Burroughs Wellcome & Co. (U. S. A.) Inc., Tuclrahoe, N. Y., a corporation of New York No Drawing. Application June 25, 1956 Serial No. 593,311

Claims priority, application Great Britain June 30, 1955 6 Claims. (Cl. 260-2475) The present invention relates to novel diquaternary compounds and to the manufacture thereof.

It has been found that compounds falling within the general Formula I have the property of blocking ganglion transmission when tested in experimental animals, for example the cat.

In this formula, R and R are the same or different and are each a cycloalkyl group (for example a cyclohexyl group), or a phenyl group which may carry one or more substituents, said substituents being halogen atoms (for example chlorine or bromine atoms), lower alkyl groups (for example a methyl group), or lower alkoxy groups (for example a methoxy group); n is an integer from two to ten; N+ is a quaternary nitrogen atom carrying two alkyl groups together having up to five carbon atoms, preferably two or three carbon atoms; N is a quaternary nitrogen atom carrying at least one alkyl group having from one to four carbon atoms and either carrying two further alkyl groups giving a total of up to nine carbon atoms, preferably a total of three to six carbon atoms, or forming part of a pyrrolidino, piperidino or morpholino ring; Y is an alkylene chain having from two to ten carbon atoms, preferably two to six carbon atoms, or N Y-N+ may be a piperazine ring in which N is a quaternary nitrogen atom carrying one alkyl group having up to four carbon atoms and N+ is a quaternary nitrogen atom carrying two alkyl groups having a total of up to four carbon atoms, the total number of carbon atoms in the alkyl groups not exceeding six; and A- is an anion of an inorganic or organic acid which may be, for example, halide or alkyl sulphate.

These compounds possess extremely powerful pharmacological properties resembling, but in many ways considerably greater than, those of known ganglion blocking agents such as hexamethonium and pentolinium. Thus, when injected into animals they lower the blood pressure and block the hypertensive action of the ganglion stimulating substance DMPP (N :N -dimethyl-N -phenyl-piperazinium iodide), while increasing the hypertensive effects of adrenaline and noradrenaline. They strongly inhibit gastric secretion and bradycardia of vagal origin and cause mydriasis and yet have little elfect on the peripheral actions of acetylcholine. In vitro they are powerful inhibitors of the peristaltic reflex of the isolated guineapig ileum but are only weak antagonists of locally applied acetylcholine.

The intensity of the various autonomic actions of the examples described in this application varies with the chemical constitution of the example, the nature of the action and the animal species in which the action is measured. Many of the compounds described are considerably more active than known ganglion blocking agents such as hexamethonium and pentolinium in inhibiting DMPP hypertension and preventing vagal bradycardia in 2,851,459 Patented Sept. 9, 1958 2 cats and in inhibiting gastric secretion in fasted rats. They have the additional advantage of a much longer duration of action.

The present invention in one aspect, therefore, comprises compounds of the general Formula I.

These compounds may be prepared by any suitable synthetic route.

According to the present invention in another aspect, compounds of the general Formula I are prepared by treating a suitable diamine of general Formula II with a quaternising agent, such as a lower alkyl halide or lower dialkyl sulphate.

In this formula, R R Y and n have the meanings given above, N is a secondary or tertiary nitrogen atom and N is a primary, tertiary or quaternary nitrogen atom, the substituents provided by the quaternising agent, together with any substituents on N and N being such as will give the desired substitution in the compound of general Formula I.

Thus, for example, N may be a tertiary nitrogen atom carrying one alkyl group having up to four carbon atoms and N may be a tertiary nitrogen atom carrying two alkyl groups having a total of from two to eight carbon atoms or may form part of a pyrrolidino, piperidino or morpholino ring, or N Y N may be a piperazine ring in which N may carry an alkyl group having from one to three carbon atoms.

The quaternisation reactions may be carried out by allowing the di-tertiary amine to stand with or by heating it With a quaternising agent such as a lower alkyl halide, in a suitable solvent such as acetone or methanol.

Compounds of the general Formula II, Where N is a secondary or a tertiary nitrogen atom and N is a tertiary nitrogen atom, may be synthesised by the following general route.

A benzhydrol (III) is reacted with a chlorohydrin (IV) in the presence of sulphuric acid, in a suitable solvent, for example benzene, to give a substance of the general Formula V. This substance is reacted with a diamine of the general Formula VI, where N is a primary or secondary nitrogen atom, in a suitable solvent, for example ethanol, to give the required Compound II.

CHOH HO (CHQHCI CHO(OH2)1;G1 N -Y--N 32 32 (III) (IV) (V) (VI) Alternatively, for those compounds of Formula II where Y represents two or three or six to ten methylene groups, an amino ether of Formula VII is reacted with the halogenoarnine of Formula VIH.

Z-Y-N In which Z is a halogen atom.

(VII) (VIII) In most of the examples given below the preparation of the iodide is described because generally the iodide is an easily crystallisable salt, but it will be understood that the methods described are also applicable to the preparation of other salts. Furthermore, one salt may be converted into any other salt by any suitable method.

The invention will now be described with reference to the following examples in which all temperatures are given in degrees centigrade.

3 Example 1 A solution of benzhydryl 2-chloroethyl ether (24.6 g.; 0.1 mol.) (Sugasawa and Fujiwara, Organic Syntheses, 1953, vol. 33, page 11) and N-(Z-diethylaminoethyl)-N- methylamine (13.0 g.; 0.1 mol.) in ethanol (25 cc.), in which anhydrous sodium carbonate (15.9 g.; 0.15 mol.) is suspended, is stirred and boiled under a reflux condenser for 16 hours. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is extracted with a mixture of dilute hydro chloric acid and ether; excess of aqueous ammonia solution is added to the acid extract and the liberated base is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulphate and the solvent is evaporated. The residual oil is fractionally distilled to give benzhydryl 2-(N-Z-diethylaminoethyl-N- methylamino)ethyl ether, boiling at 152/0.06 mm., n 1.5307.

A solution of the base (1.3 g.) and methyl iodide (1.3 cc.) in acetone cc.), on standing at room temperature deposits an oil which is crystallised from methanol to give N -(Z-benzhydryloxyethyl)-N :N -diethyl- N :N :N -trimethylethylene-1 :Z-diammonium di-iodide, melting at 156-157, with decomposition.

Example 2 A solution of benzhydryl 3-chloropropylether (6.5 g.; 0.025 mol) (prepared by the method quoted in Example 1) and N-(2-diethylaminoethyl)-N-methylamine (5.2 g.; 0.04 mol.) in ethanol (5 cc.) is boiled under a reflux condenser overnight and worked up by the method of Example 1 to give benzhydryl 3-(N-Z-diethylaminoethyl-N- methylamino)propyl ether, boiling at 184186/ 0.03 mm., n 1.5252.

A solution of the base (1.0 g.) and methyl iodide (2 cc.) in methanol (4 cc.) is boiled under a reflux condenser for 16 hours and the reaction mixture is cooled. The crystalline product, which is separated by filtration, is recrystallised from aqueous methanol to give N -(3- benzhydryloxypropyl) N zN diethyl N cN aN -trimethyl-ethylene-l:Z-diammonium di-iodide, melting at 210-212, with decomposition.

Example 3 Example 4 N -(4-benzhydryloxybuty1)-N -methylpiperazine, boiling at 190192/0.1 mm., 11, 1.5461, is prepared from benzhydryl 4-chlorobutyl ether (prepared by the method quoted in Example 1) and N-methylpiperazine, by the method of Example 3.

N (4 benzhydryloxybutyl) N :N :N trimethylpiperazinium di-iodide, decomposing over the range 210270, after crystallisation from aqueous ethanol, is obtained therefrom by the method of Example 2.

Example 5 Benzhydryl 4-(N-2-di-n-butylaminoethyl-N-methyl)- aminobutyl ether, boiling at 222224/0.09 mm., 11 1.5146, is prepared from benzhydryl 4-chlorobutyl ether and N-(Z-di-n-butylaminoethyl)-N-methylamine by the method of Example 2.

N (4 benzhydryloxybutyl) N :N di n butyl- N :N :N -trimethylethylene-1:Z-diammoniurn di-iodide (containing 0.6% water of crystallisation), melting at 4 126-128, is obtained therefrom by the method of Example 2, with the modification that the quaternisation reaction solution is evaporated to dryness and the residue is crystallised from a mixture of methanol and acetone.

Example 6 Benzhydryl 4 (N methyl N 2 pyrrolidinoethyl)aminobutyl ether, boiling at 197200/ 0.05 mm., n 1.5420, is prepared from benzhydryl 4-chlor0butyl ether and N-methyl-N-(Z-pyrrolidinoethyl)amine, by the method of Example 2.

N (4 benzhydryloxybutyl) N :N :N trimethylethylene-l-pyrrolidinium di-iodide, melting at 179-181, with decomposition, after crystallisation from a mixture of methanol and acetone, is obtained therefrom by the method of Example 5.

Example 7 Benzhydryl 4-(N-methyl-N-Z-piperidinoethyl)aminobutyl ether, boiling at 205207/0.1 mm., n 1.5370, is prepared from benzhydryl 4-chlorobutyl ether and N- met'nyl-N-Z-piperidinoethyl)amine, by the method of Example 2.

N (4 benzhydryloxybutyl) N :N :N trimethylethylene-l-arnmonium-Z-piperidinium di-iodide, melting at 186188, with decomposition, after crystallisation from a mixture of methanol and acetone, is obtained therefrom by the method of Example 5.

Example 8 Benzhydryl 4 (N methyl N 2 morpholinoethyl)aminobutyl ether, boiling at 202-204/0.04 mm., n 1.5394, is prepared from benzhydryl 4-chlorobutyl ether and N-methyl-N-(2-morpholinoethyl)amine by the method of Example 2.

N (4 benzhydryloxybutyl) N :N :N trimethylethylene-1-ainmonium-2-morpholinium di-iodide, melting at ZOO-201, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 2.

Example 9 4 (N 2 diethylaminoethyl N methyl) aminobutyldi (4-methylphenyl)methyl ether is prepared as a yellow oil from 4-chlorobutyl di-(4-methylphenyl)methyl ether (prepared by the method quoted in Example 1) and N- (Z-diethylaminoethyl)-N-methylamine, by the method of Example 3.

N zN diethyl N :N :N trimethyl N [4 di- (4 methylphenyl)methoxybutyl] ethylene 1:2 diammonium di-iodide, melting at 218-219, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 2.

Example 10 4 (N 2 diethylaminoethyl N methy1)aminobutyl di (2 methylphenyl)methyl ether, boiling at 203205/0.1 mm., 11 1.5289, is prepared from 4- chlorobutyl di-(2-methylphenyl)methyl ether (prepared by the method quoted in Example 1) and N-(2-diethylaininoethyl)-N-methylamine, by the method of Examp e 3.

N zN diethyl N :N :N trimethyl N [4 di- (2 methylphenyl)methoxybutyl] ethylene 1:2 diammonium di-iodide, melting at 181-182", with decomposition, after crystallisation from ethanol, is obtained therefrom by the method of Example 5.

Example 1] A solution of benzhydryl 4-chlorobutyl ether (11.0 g.) in an ethanolic solution of methylamine (60 g.; 33% w./w.) is heated at in a sealed tube for 16 hours. The solution is concentrated to low volume and extracted with a mixture of dilute hydrochloric acid and ether. An excess of aqueous ammonia solution is added to the acid extract and the liberated base is extracted with ether. The ether extract is washed with a little water, dried over anhydrous sodium sulphate and evaporated. The residual oil is fractionally distilled to give benzhydryl 4-methylaminobutyl ether, boiling at 140-142/0.25 mm., n .550.

A solution of freshly-prepared 1-bromo-6-morpholinohexane (4.8 g.; 0.019 mol.) (prepared from 1:6-dibromohexane via 6-morpholino-l-phenoxyhexane by the method used, for example, by Marvel, Zartman and Bluthardt, Journal of the American Chemical Society, 1927, volume 49, page 2302), benzhydryl 4-methylaminobutylether (5.1 g.; 0.019 mol.) and triethylarnine (1.9 g.; 0.019 mol.) in ethanol (20 cc.) is boiled under a reflux condenser for 7 hours. The solvent is evaporated, an excess of aqueous ammonia solution is added to the residue and the liberated base is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulphate, and the solvent is evaporated. The residual oil is fractionally distilled to give benzhydryl 4-(N-methyl-N-6-morpholino-hexyl) aminobutyl ether, boiling at 242- 246/0.5 mm. I

N (4 benzhydryloxybutyl) N :N :N trimethylexamethylene 1 ammonium 6 morpholinium diiodide is obtained therefrom, as a gum, by the method of Example 5.

Example 12 Benzhydryl 3 (N methyl N 2 morpholinoethyl)- aminopropyl ether, boiling point 187-189/0.07 mm., is prepared by the method of Example 3, with the modification that excess of aqueous ammonia is added to the residue after evaporation of the reaction mixture, extraction with dilute hydrochloric acid being omitted.

N (3 benzhydryloxypropyl) N :N :N trimethylethylene 1 ammonium 2 morpholinium di iodide, melting point 203-204", with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 2.

A solution of the di-iodide (6.0 g.) in aqueous ethanol (100 ml.; 70% w./v.) is passed down a column 15 x 1.3

' cm.) of Dowex 2 ion-exchange resin, in the hydroxyl form and the column is subsequently washed with aqueous ethanol (70% v./v.). The eflluent is neutralised with dilute hydrochloric acid, the solvent is evaporated under reduced pressure and the residue is triturated with acetone. The resulting solid is crystallised from a mixture of methanol and acetone to give N -(3-benzhydryloxypropyl) 1 :N :N trimethylethylene 1 ammonium- Z-morpholinium dichloride, as shimmering leaflets, melting point 229, With decomposition.

Example 13 Benzhydryl 4 (N 2 diethylaminoethyl N methyl)- aminobutyl ether, boiling point 194/0.9 mm., 11 1.5222, is prepared by the method of Example 4, with the modification employed in Example 12.

N (4 benzhydryloxybutyl) N :N diethyl- N :N :N trimethylethylene 1:2 diammonium diiodide, melting point 190-191 with decomposition, after crystallisation from methanol, is obtained therefrom by the method of Example 2.

Example 14 in Example 1.

N [4 di (4 chlorophenyl)methoxybutyl]- N :N :N trimethylethylene 1 ammonium 2 piperidinium di-iodide, melting point 173-175, with decomposition, after crystallisation from aqueous methanol, is obtained therefrom by the method of Example 2.

Example 16 A solution of the ditertiaryamino base of Example 13 (4.0 g.) in acetic acid (20 ml.) is fully hydrogenated in the presence of platinum oxide (1.0 g), under atmospheric conditions. The catalyst is filtered ofi, the solvent is evaporated under reduced pressure, and the residue is shaken with an excess of dilute aqueous ammonia solution and ether. The ether extract is washed with water, dried over anhydrous sodium sulphate, and evaporated. The residual oil is fractionally distilled to give 4-(N-2- diethylaminoethyl N methyl)aminobutyl dicyclohexylmethyl ether, boiling point 188-190/0.7 mm.

N' zN diethyl N (4 dicyclohexylmethoxybutyl)- N :N :N trimethylethylene 1:2 diammonium diiodide, melting point 188-189, with decomposition, is obtained therefrom by the method of Example 2, with the modification that the reaction solvent is evaporated and the residue is crystallised from a mixture of methanol and ethyl acetate.

Example 17 Benzhydryl 3 (N 3 morpholinopropyl)aminopropyl ether, boiling point 198-201 0.1 mm., n 1.5440, is prepared from benzhydryl 3-chloropropyl ether and 3- morphol-inopropylamine by the method of Example 12, with the modification that a solution of the chloro ether (0.025 mol.) in benzene is added dropwise to a stirred solution of the diamine (0.05 mol.) in benzene, during a period of 1 /2 hours.

A solution of the base (5.0 g.) and methyl iodide (10 ml.) in methanol (50 ml.) is boiled under a reflux condenser for 16 hours, in the presence of anyhydrous sodium carbonate (10 g.). The reaction mixture is filtered, the solvent is evaporated, and the residue is crystallised from a mixture of methanol and acetone to give N (3 benzhydryloxypropyl) N zN zN trimethylene 1 ammonium 3 morpholinium di iodide, melting point 191-l92, with decomposition.

Example 18 Benzhydryl 3 (N 3 morpholinopropyl)aminobutyl ether, boiling point 199-203/0.08 mm., n 1.5400, is prepared by the method of Example 17.

N (4 benzhydryloxybutyl) N :N :N trimethyltri'methylene 1 ammonium 3 morpholinium diiodide, melting point 177-178, with decomposition, after crystallisation from a mixture of methanol and acetone, is obtained therefrom by the method of Example 17.

N (4 benzhydryloxybutyl)-N :N :N -trimethyltrimethylene-1-ammonium-3-morpholinium dichloride, containing 6.1% of water of crystallisation and sintering at ca. and melting at 203-205", after crystallisation from a mixture of ethanol and acetone, is obtained from the di-iodide by the method of Example 12.

Example 19 A solution of benzhydryl 4-piperidinobutyl ether (6.46 g.; 0.02 mol.) (prepared by the method of Example 12) and 3-chloro-propyltrimethylammonium bromide (4.8 g.; 0.022 mol.) (prepared from 1-bromo-3-chloropropane and trimethylamine) in n-propanol (50 ml.) is boiled under a reflux condenser for 60 hours. The solvent is evaporated and the residue is triturated with acetone;

t 7 V the resulting solid is crystallised from a mixture of methanol and ethyl acetate to give N :N :N -trimethyl- N -.(.6:6-diphenyl-5-oxahexyl)trimethylene 1 piperidinium-3-ammonium dibromide, containing 1 /2 mols. of water of crystallisation, melting point l66-167.

Example 20 A solution of the ditertiaryamino base of Example 13 (1.0 g.) and ethyl iodide (2 ml.) in ethanol (5 ml.) is boiled under a reflux condenser for 24 hours. The solvent is evaporated and the residue is triturated with dry ether. The resulting amorphous solid is crystallised from a mixture of acetone and ethyl acetate to give N (4 benzhydryloxy butyD-N :N :N :N -tetraethyl-N methylethylene-l :2-di-ammonium di-iodide, melting point 154155.

What I claim is:

1. Compounds of the general formula:

R7 wherein R and R are selected from the class consisting of cyclohexyl, pheny'l, halogenophenyl and lower alkyl phenyl groups, n is an integer from 2 to 10, N is a quaternary nitrogen atom containing two lower alkyl groups, N"' is a quaternary nitrogen atom selected from the class consisting of those containing three lower alkyl groups and those forming part of lower alkyl pyrrolidino, lower alkyl piperidino and lower alkyl morpholino groups, Y is an alkylene chain having from 2 to 10 carbon atoms, and N -YN+ together constitute a piperazine ring, wherein N+ is a quaternary nitrogen atom containing one lower alkyl group and N+ is a quaternary nitrogen atom containing two lower alkyl groups, and A- is the anion of a therapeutically acceptable acid.

2. Therapeutically acceptable salts of N -(3-benzhydryloxypropyD-N zN zN -trimethylethylene l ammonium-Z-morpholine.

3. Therapeutically acceptable salts of N -(4-benzhydryloxybutyl) N zN zN -trimethylethylene 1 ammonium-2-morpholine.

4. Therapeutically acceptable salts of N -(4-benzhydryloxybutyl) N zN zN trimethylethylene-l-arnmonium-Z-pyrrolidine.

5. Therapeutically acceptable salts of N -(4-benzhydryloxybutyl) N :N diethyl N :N :N trimethylethylene-1 :Z-diammonium.

6. Therapeutically acceptable salts of N -(4-benzhydryloxybutyl) N :N :N trimethyltrimethylene-l-ammonium-S-morpholine.

No references cited. 

1. COMPOUNDS OF THE GENRAL FORMULA:
 2. THERAPEUTICALLY ACCEPTABLE SALTS OF N1-(3-BENXHYDRYLOXYPROPYL)-N1:N1:N2-TRIMETHYLETHYLENE - 1 - AMMONIUM-2-MORPHOLINE. 